Klinefelter syndrome (KS), a genetic disorder that occurs in 1/1000 males, is defined by the abnormal chromosome karyotype 47.XXY (extra X chromosome), and has characteristic physical and cognitive phenotypes evident in childhood. The KS physical phenotype includes testicular failure (androgen deficiency) and tall stature. The KS neurocognitive phenotype includes diminished motor function and language-based learning difficulties. The KS behavioral phenotype involves poor self-image and shyness. The neurodevelopmental deficits associated with KS likely reflect the influence of both androgen deficiency and genetic factors on development and represent a major impediment for living a normal life with KS. It is the goal of this clinical trial to determine whether this burden can be reduced by treatment early in childhood with androgen replacement. Androgen replacement is standard in adolescent and adult KS males but has not been used in younger, prepubertal KS boys. The Phase I study will establish that the androgen oxandrolone, an FDA-approved medication for children, is also safe in prepubertal KS boys. The Phase II study is the randomized clinical trial, in which we plan to study the effects of childhood androgen replacement on motor and cognitive aspects of the KS phenotype that may result from childhood androgen deficiency. This randomized, placebo-controlled study tests a novel intervention in this population: low-dose androgen (oxandrolone) treatment for two years in KS boys (n=120), ages of 4-12 years. We predict that KS boys treated with androgen for 24 months will have improved muscle strength, compared to the placebo-treated KS boys. Second, we predict that KS boys treated with androgen for 24 months will have improved aspects of motor function including response speed, simple repetitive movement, and complex nonrepetitive motor action, compared to the placebo-treated KS boys. Third, we predict that KS boys treated with androgen (oxandrolone) for 24 months will have improved aspects of language, including verbal memory and verbal fluency and fourth, we predict that KS boys treated with androgen for 24 months will have improved aspects of simple and complex attention, compared to the placebo-treated KS boys. RELEVANCE OF THIS RESEARCH: KS is well suited for interventional studies because testicular failure is nearly universal in this disorder. Early androgen replacement is a reasonable, appropriate, and safe research treatment option in this androgen-deficient population. Therapeutic interventions for this relatively common disorder have not been forthcoming, and this proposal represents a unique opportunity to replace a missing hormone and potentially improve motor function and cognition. If successful, androgen replacement in the clinical management of KS would commence early in childhood rather than adolescence or adulthood.